The main objective of this project is to gain insight into the progression of gray matter (GM) atrophy in multiple sclerosis (MS) patients through advanced magnetic resonance imaging (MRI) and newly developed image analysis methods. Gray matter tissue damage is a major component of overall MS pathology in the brain. However, relatively little is known about GM pathology in MS patients because the majority of focal GM lesions cannot be detected with MRI. GM atrophy, on the other hand, can be measured reliably with accurate image analysis methods and can be used to estimate the total extent of destructive GM pathology. GM atrophy is likely due to a combination of severe tissue damage in the GM itself and neurodegeneration secondary to damage in the white matter (WM). The relative contributions of each and how these change over the course of disease are unknown. In this project, a longitudinal MRI study of 70 MS patients and 17 healthy controls will be extended (from 9 to 14 years) and new image analysis methods, based explicitly on findings from post-mortem MRI/pathology correlation studies, will be developed and applied in order to (1) Determine the relationship between specific types of pathologically-validated, MRI-defined WM lesion subtypes and GM atrophy;(2) Assess the degree to which specific types of pathologically-validated, MRI-defined damage in normal-appearing brain tissue regions are related to GM atrophy;and (3) Determine the pathologic and clinical significance of GM atrophy in post-mortem and long-term follow-up studies. The first two aims seek to identify new in vivo MRI markers that are strongly correlated to GM tissue damage based on the pathologic correlates of MRI characterstics in MS brains post-mortem. Application of these new markers in the longitudinally-followed patient group will help to elucidate the mechanisms and time course of GM atrophy progression. The third aim will help to validate GM atrophy measurements. In the first part of Aim 3, post-mortem MRI-guided pathology will be used to determine how cortical thinning relates to focal pathology in GM. The second part of Aim 3 will use data from the longitudinal study to determine how overall GM atrophy and regional changes in cortical thickness relate to the progression of disability and cognitive deficits in patients with MS. Through discovery and validation of new MRI markers of MS pathology in gray matter, this study will lead to a better understanding of MS and improved tools for patient monitoring and evaluation of potential neuroprotective therapies.